Processes for the production of n-acylated amino-substituted carboxylic acids



Patented July 18, 1950 2,515,320

{UNITED STATES PATENT OFF-ICE PROCESSES FOR THE" PRODUCTION OF N ACYLATED AMINO-SUBSTITUTED CAR- ,-,BOXYLIC ACIDS 'I'f' Herman Sokol, Hasbrouck Heights;'N. J} assigncr to Heyden Chemical Corporation, New York, N. Y-., a corporation of Delaware No Drawing. Application November 6, 1946,

Serial No. 708,196 4 Claims. (Cl. 260*513) 1 2 a The present invention relates to N-acylated most exclusively of the lower-boiling symmetrical amino-substituted carboxylic acids in which the anhydride which would be expected from the disamino radical is substituted by an wac yl radical proportionation reaction. Some decomposition and to processes for the roduction of such amides of the amide group also occurs at higher temacid compounds. In one of its more specific as peratures and cannot be prevented in most cases. pects, the invention relates to an improved Mixed amide-anhydrides also react with water method for converting a mixed amide-anhydride and with amines; In converting the mixed of siich an acid to the amide -acid, for example, amide-anhydride to the amide-acid, by either acetylanthranilic-acetic anhydride to .acety'lheating, distillation, water or aniline, consideranthranilic acid; In one of its preferred em able hydrolysis of the acyl group attached to the bodiments, the invention relates to the Drod1i0- amino substituent of the acid invariably results.

tion of N-acetylaiith'ranilic acid by the reaction Thus in converting N-acetylanthranilic-racetlc of N-acetylanthranilic-acetic anhydride with anhyd'ride to N-acetylanthranilic acid by means acetic acid to form the desired N-acetylanof heating,'disti11ation,- or hydrolysis by water,

thranilic acid and acetic anhyd'ride. V anthranllic acid is formed in substantial quan The present application is 2, ccntinuatio'n intitlefl. p P Of y prior Copehdmg application Serial lIt isan object of the present invention to pro= N 582,408, d a h 12,1945,which s ss ride a process for the production of amide-acids as Patent No. 2,423,569,- and which in turn is a onforming to thegeneral formula:

continuation-in-part of and substitute for my apg I a plication Serial No. 540, 133, filed August 11, 1944, COOH which application was abandoned. in which Y is an alkyl radical and R is a hydro- Heretofore a, wide variety of mixed anhydri carbon radical, which may be either aliphatic or of N-acylated amino-substituted carboxylic acids aromatic, from mixed amide-anhydrides com have been prepared. Such a mixed anhydride is forming-to the general formula N-acetylanthranilic-acetic ahhy'dride, which can 1 7 h a 7 A I be made by reaction of anthr-anilic acid with a YCONH'R CO-OOCY large excess of acetic anhydride and by reaction It is a furtherobje'ct of the invention to prowith ketene. These two reactions are reprevide-siich a process in which there will be no sentable as follows: so substantial decomposition or hydrolysis so that /0C -*-CHi" NH; 2 0' --v" '2 cihcoon -Nii o-o oiia 00-6113 -co- -0H CO--O-"-OC'==CHa Acetic anhydride +2OC==CH1-/" Anthrsnilic acid Ketcne N-acetylanthranilicacetic snhydride The reactions of ketene with glycine (aminosome replacement of the acyl group joined to the acetic acid), leucine and anthr'anilic acid (ortho- 'ai hirio radical by a hydrogen radical takes place aminobenzoic) to produce the corresponding It is a further specific object of the present inmixed amide-anhydi'ides are disclosed in Gaylor vention to provide a process for the conversion Patent No. 2,236,125. a of mixtures containing N-acetyianthraniiic- Mixed amide-anhydrides are unstable comacetic anhydride, such as are obtained by reac p nds, m cases p p r n ins on ticns of anthranil'ic acid with acetic anhydride fl d into the resp symmetrlcal a yand with ketene, to N-acetylanthranilic 'acid and dri es. For x mp e, ylan hr mli ic aceti anhydride, without substantial decomposianhydride disproportionates into N-acetylanthration or hydrolysis of the compound to form nilic anhydride and acetic anhydride. On heatanthranilic acid or other undesirable products.

ing, for example, to temperatures above approxi- Other specific objects of this invention are to mately 100 C., the disproportionation is greatly provide improved processes for the production of accelerated and, when distilled at such tempera- N acylated amino-substituted carboxylic acids tures, the distillate first appearing consists alsuch asN-acylated aliphatic and aromatic amino acids, some of which may be used as such or as intermediates for the production of other compounds.

Otherobjects and advantages of the invention, some of which are referred to specifically hereinafter, will be apparent to those skilled in the art to which the invention pertains.

In accordance with a preferred process for the practice of the invention, acetic acid, preferably glacial acetic acid, is added to N-acetylanthranilic-acetic anhydride, or another of the mixed acetamide-an-hydrides specified herein, or a reaction mixture containing such mixed amide- 4 butyric, pentanoic, hexanoic, dodecanoic, octadecanoic acids and the like, may be used. Such mixed amide-anhydrides may be obtained by reaction of ketene homologues such as methylketene, ethylketene, etc.) or corresponding acid anhydrides or acyl chlorides, with amino-substituted carboxylic acids. In the conversion of such mixed amide-anhydrides, the corresponding acid may be used instead of acetic acid to produce the corresponding anhydride as one of the reaction products. Thus, N-propionyl-paminobenzoic acid may be obtained by treating N-propionyl-p-aminoben-zoicpropionic anhydride anhydrides, and the resulting mixture is subjected:

to heating at a temperature between approximately 20 C. or slightly lower and approximately 90 C. or slightly higher. In this heating, the re-' action which occurs in the case of N-acetylanthranilic-acetic anhydride and acetic acid may be represented as:

NH-O -0313 01130 OOH N-Acetylanthranilic- Acetic acetic anhydride acid /0 coon CHQCO N-acetylanthranilic Acetic acid anhydride After the heating, the acetic anhydride which is formed is removed from the reaction mixture by distillation, preferably at subatmospheric pres- I sure. The residue which remains may then be subjected to a second treatment with acetic acid, if the conversion of the N-acetylanthranilicacetic anhydride has not proceeded to the desired extent in the first treatment. The resulting N-acetylanthranilic acid is then recovered and subjected to further conventional purification, if desired.

By means of the above process it is possible to avoid substantial decomposition to anthranilic acid, which would result if the N -acetylanthranilie-acetic anhydride were decomposed by heat or by water to N-acetylanthranilic acid. Furthermore, the acetic anhydride represents a byproduct of considerable value. If water were used for the hydrolysis of the mixed amide-anhydride the byproduct would be the less desirable acetic acid. The process of the invention finds greater usefulness in connection with the production of N- acetylanthranilic acid from anthranilic acid and ketene, in which process the formation of some N-acetylanthranilic acetic anhydride cannot be prevented, rather than in the process of producing N-acetylanthranilic acid from anthranilic acid and acetic anhydride, acetyl chloride or other acetylating agent, in which the acetylation can be, controlled so as to yield only N-acetylanthranilic acid. By using the process of the invention, the excess ketene which is consumed in the production of the intermediate N-acetylanthranilic-acetic anhydride is recovered as acetic anhydride.

Although the foregoing description refers particularly to N-acetylanthranilic-acetic anhydride and similar mixed acetamideanhydrides and conversion of such compounds to acetic anhydride and amide-acids by means of acetic acid, the corresponding mixed anhydrides of other acids, such as those of propionic, butyric, isowith propionic acid. Using the generic formulae hereinabove adopted, the general reaction may be represented as:

Y-C 0NHR-C 0-0-0 C-Y Y-COOH Y-00 -NH-R-0 -0H /0 "'Y-c0. When conducting this-reaction the acid-whichis added for the purpose of effecting the conversion is generally that whichcorresponds ,to-the lowestboiling of the two anhydrides which would be expected to form on disproportionation, since it is that anhydride which is distilled ofi, leaving the amide-acid as residue. These latter maybe distilled or purified subsequently in other manners, Beside the simple amino-substituted aliphatic and aromatic acids (anthranilic-and .p-aminobenzoic acids, glycine and leucine) referred to above and in the examples, the, process of the invention is applicable to the production of awide variety ofother N-acylated amino-acids,.including N-acyl derivatives of the following acids:

(CH3)2OHGH(NHB)COOH I Valine onoiononionmmjooon' Leucine v C2H5(CH3)OHCH(NH2)OQOH Isoleucine olnlonionmnocoon Phenylalanine CHBS(CH2)2OH(NH2)COOH Methionine onsonononmnoooon Threonine Nniomcnzomonionmnoo00H Lycine I Nniomongcngonmnocoon Ornithine NHaC (=NH)NHCH2OHCH2 (NH2) 0 0 OH Arginine CH3CH2CH2CH2CH(NH2)COOH Norleucine ooon-onzonmrmooon v Aspartic acid NmooNnonzomcmcnrNnoo00H Citrulline Y Q B ea -c o Proline I Tryptophane HO-NH H on v onronmneooon' Histidine v g I I l Y HOQ-OO-oHZOHOOOH v BITE-[2 I I I Thyroxine HSCH2CHNH2(COOH) Cysteine s-omonmneooon -CH2CH(NH2)COOH I v Cystine coon-omcmonovnnooon Glutamic acid HOOH2CH2(NH2)COOH Serine HOCsH4OHzCH(NHz)OOOH Tyrosine coon-omenom-onmnoooon Hydroxyglutamic acid I HOOK-47H:

H2NHCH-COOH Hydroxyproline In connection with some of the foregoing acids which contain other functional groups, namely hydroxyl (OII) and mercaptyl (--SI-I) groups, these groups will also be acylated. Reference 1s respectfully directed to my application Serial No.

582,408 (Patent No. 2,423,569) which is directed specifically to processes of this character. Acylation of all basic nitrogen radicals will result, if the L acid, for example, lysine, ornithine and arginine, contains more than one such group.

Although the process is described herein specifically with reference to amino-substituted acids, that is, acids in which the substituent radical is an otherwise unsubstituted -NHz radical it is obvious that the process is likewise applicable to acids containing such radicals which are further substituted, that is, to imino-substituted acids containing the radical --NH having one replaceable hydrogen atom and generally to all acids containing basic nitrogen radicals.

The temperatures at which the conversion of the mixed amide-anhydride is effected in accordance with this invention are generally substantially below the boiling point at atmospheric pressure of the anhydride that is formed and at or above room temperature. Thus, in the case of N-acetylanthranilic-acetic anhydride that is treated with acetic acid in accordance with my invention, a preferred temperature is 90 C., and a subatmospheric pressure is used thereafter so that the resulting acetic anhydride may be distilled off at approximately that temperature. The temperatures which are used are substantially below the decomposition point of the mixed amide-anhydride and thereby the danger or possibility of decomposition of the N-acylated amino Furthermore, since no substantial r anthranilic acid from anthranilic acid and ketene and from anthranilic acid and an excess of acetic anhydride or other acetylating agent. When acetylating with ketene, in contradistinction to acetic anhydride, it is difficult to avoid the formation of substantial amounts of N-acetylanthranilic-acetic anhydride. The process of the invention is adapted to the treatment of mixtures consisting entirely of N-acetylanthranilicacetic anhydride as well as to mixtures containing smaller proportions of said compound, such, for example, as mixtures obtained by reaction of anthranilic acid with an excess of acetic anhydride that is insufiicient to effect complete conversion to the mixed amide-anhydride.

In the conventional method of producing N- acetylanthranilic acid, the acetylation of anthranilic acid is generally carried to a point short of complete acetylation of all amino radicals since further acetylation would result in the substitution of acetyl radicals into the carboxyl group with the formation of N-acetylanthranilicacetic anhydride. This is undesirable because, when treated with water, the excess acetic anhydride Which was used is converted to acetic acid and represents a loss of acetic anhydride in the process. As a result, in the conventional method, the yields are lower, and the concentration of acetylating agent, the reactiontemperatures and periods which are used must be more carefully controlled than in the process in whichN-acetylanthranilic acid is produced by reaction of anthranilic acid with an excess of acetic anhydride or with ketene. As hereinabove stated, the reaction of ketene with anthranilic acid proceeds directly to produce N-acetylanthranilic-acetic anhydride rather than stepwise to produce first N-acetylanthranilic acid and then N-acetylanthranilic-acetic anhydride. Furthermore, the process in which N-acetylanthranilic-acetio anhydride is formed requires no recovery and recycling of unreacted anthranilic acid from the reaction product, which is a difficult and expensive procedure. In the production of N-acetylanthranilic acid by the combination of processes for the production of N-acetylanthranilic-acetic anhydride, either solely or only as a portion of the reaction product, together with the conversion of the N-acetylanthranilicacetic anhydride to N-acetylanthranilic acid and acetic anhydride by reaction with substantially anhydrous acetic acid, a product of extremely high purity is obtained in substantially theoretical yields without the necessity for successive crystallization procedures and extensive procedures for the recovery of materials from mother liquors, and the excess acetylating agent which was used to make the N-acetylanthranilicacetic anhydride is recovered as acetic anhydride rather than as acetic acid.

Preferred methods of practicing the general process of my invention are illustrated in the specific examples which follow:

Example 1.-N-acetyldnthranilic acid N-acetylanthranilic-acetic anhydride was prepared by dissolving 137 g. (approximately 1 mole) of anthranilic acid in 500 ml. of anhydrous ether and this solution was saturated with ketene until slightly more than 84 g. (approximately 2 moles) of ketene were absorbed. The ether was evaporated from the solution on a water bath at 50-60 C. and there remained the single reaction product, N-acetylanthranilic-acetic anhydride, in the form of a viscous oil. The oil thus obtained was treated with 240 g. (approximately 4 moles) of glacial acetic acid and the mixture was agitated at 90 C. for 2 hours. The mixture was then subjected to a reduced pressure of mm. of mercury with a maximum bath temperature of 90 C. and the acetic acid and acetic anhydride were distilled from the mixture. After stripping until no more distillate was obtained, the solid residue was stirred thoroughly with 100 g. of petroleum ether and filtered. The recovered N-acetylanthranilic acid was dried and weighed 147 g. This represents a yield of 82% of the theoretical.

The petroleum ether was stripped from the filtrate by heating the filtrate on a water bath, and the residual oily mixed anhydride was treated again with a g. portion of glacial acetic acid. The recovered N-acetylanthranilic acid from the second treatment weighed 21 g.

The total recovery of N-acetylanthranilic acid was 168 g., which is 94% of the theoretical. The distillates from the above operations contained 90 gpof acetic anhydride, which is 88% of the theoretical.

Example 2.-N-acetylglycine (aceturic acid) Aceturic-acetic anhydride was prepared by suspending '75 g. (approximately 1 mole) of glycine in 500 ml. of anhyrous acetone and saturating the mixture with ketene until a homogeneous solutionresulted. The acetone was evaporated from the solution on a water bath at to C. and. there remained a viscous oil, which was principally aceturic-acetic anhydride. The oil thus obtained was treated with 240 g. (approximately 4 moles) of glacial acetic acid by agitating at 90 C. for 2 hours. This mixture was then subjected to a reduced pressure of 20 mm. of mercury at a bath temperature of 90 C., and the acetic acid and acetic anhydride were rapidly distilled from the mixture to leave a solid residue consisting of approximately to N-acetylglycine (aceturic acid) and unconverted mixed anhydride. The solid was then stirred well with 200 g. of ether and filtered. The recovered solid weighed 99 g. and its melting point (206 C.) and analysis demonstrated it to be pure aceturic acid. A yield of 84.5% was thus obtained.

The ether filtrate was heated on a water bath to evaporate the ether and the residual oily mixed anhydride was treated as described in Example 1 with 50 g. of glacial acetic acid. The recovered aceturic acid from this second treatment weighed 12 g., which represents a total recovery of 111 g. of aceturic acid, or an overall yield of The distillates from the two operations contained 92 g. of acetic anhydride, which is equivalent to 90% of the theoretical amount.

Ketene (CHzCO) may be considered the result of removing one molecule of water from one molecule of acetic acid, and acetic anhydride (CI-I3COOOCCH3) may be considered as the result of removing one molecule of water from two molecules of acetic acid. Accordingly, both ketene and acetic anhydride are to be understood by the term anhydride of acetic acid, as used in this specification.

Inasmuch as the foregoing description comprises preferred embodiments of the invention it is to be understood that the invention is not limited thereto and that conventional alterations and modifications may be made therein without departing substantially from the invention,

8 l whose scope is to be limited. solely by the appended claims.

I claim:

1. A process for the production of an N- acetylated amino-substituted carboxylic acid selected from the group consisting of N-acetyl glycine, valine, leucine, isoleucine, phenylalanine, methionine, threonine, lysine, ornithine, arginine, norleucine, aspartic acid, citrulline, proline, tryptophane, histidine, thyroxine, cysteine, cystine, glutamic acid, serine, tyrosine, anthranilic acid and para-aminobenzoic acid, which comprises the reaction of a mixed anhydride of the N- acetyl amino-substituted carboxylic acid and acetic acid with suchan amount of substantially anhydrous acetic acid that at least approximately 4 molecular proportions of acetic acid are present for each molecular proportion of the mixed anhydride, whereby the N-acetyl aminosubstituted carboxylic acid and acetic anhydride are formed, and subsequently recovering the resulting N-acetyl amino-substituted carboxylic acid.

2. A process for the production of N-acetylanthranilic acid which comprises the reaction of N-acetylanthranilic-acetic anhydride with substantially anhydrous acetic acid in such amount that at least approximately 4 molecular proportions of acetic acid are present for each molecular proportion of N-acetylanthranilic-acetic anhydride, whereby N-acetylanthranilic acid and acetic anhydride are formed. and subsequently recovering the resulting N-acetylanthranilic acid.

3. A process for the production of N-acetylglycine which comprises the reaction of N-acetylglycine-acetic anhydride with substantially anhydrous acetic acid in such amount that at least approximately 4 molecular proportions of acetic acid are present for each molecular proportion of N-acetylglycine-acetic anhydride, whereby N- acetylglycine and acetic anhydride are formed, and subsequently recovering the resulting N- acetylglycine.

4. A method of producing N-acetylanthranilic acid, which comprises reacting N-acetylanthranilic-acetic anhydride with substantially anhydrous acetic acid in a ratio of approximately 1 mole of N-acetylanthranilic-acetic anhydride to 4 moles of acetic acid at approximately 90 C. for approximately 2 hours, and subsequently recovering the resulting N-acetylanthranilic acid.

HERMAN SOKOL.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Dakin: J. Biol. Chem., Vol. 82 (1928), page 443.

Bergmann et al.: Ber. deut. Chem," vol. 63 (1930) pages 437-439.

Chattaway: J. Chem. Soc." (London), 1931, pages 2495-2496.

I-Ierbstet al.:

Organic Syntheses, vol. 19 (1939) ,pag'e's 4-5. v 

1. A PROCESS FOR THE PRODUCTION OF AN NACETYLATED AMINO-SUBSTITUTED CARBOXYLIC ACID SELECTED FROM THE GROUP CONSISTING OF N-ACETYL GLYCINE, VALINE, LEUCINE, ISOLEUCINE, PHENYLALANINE, METHIONINE, THREONINE, LYSINE, ORNITHINE, ARGININE, NORLEUCINE, ASPARTIC ACID, CITRULLINE, PROLINE, TRYPTOPHANE, HISTIDINE, THYROXINE, CYSTEINE, CYSTINE, GLUTAMIC ACID, SERINE, TYROSINE, ANTHRANILIC ACID AND PARA-AMINOBENZOIC ACID, WHICH COMPRISES THE REACTION OF A MIXED ANHYDRIDE OF THE NACETYL AMINO-SUBSTITUTED CARBOXYLIC ACID AND ACETIC ACID WITH SUCH AN AMOUNT OF SUBSTANTIALLY ANHYDROUS ACETIC ACID THAT AT LEAST APPROXIMATELY 4 MOLECULAR PROPORTIONS OF ACETIC ACID ARE PRESENT FOR EACH MOLECULAR PROPORTION OF THE MIXED ANHYDRIDE, WHEREBY THE N-ACETYL AMINOSUBSTITUTED CARBOXYLIC ACID AND ACETIC ANHYDRIDE ARE FORMED, AND SUBSEQUENTLY RECOVERING THE RESULTING N-ACETYL AMINO-SUBSTITUTED CARBOXYLIC ACID.
 2. A PROCESS FOR THE PRODUCTION OF N-ACETYLANTHRANILIC ACID WHICH COMPRISES, THE REACTION OF N-ACETYLANTHRANILIC-ACETIC ANHYDRIDE WITH SUBSTANTIALLY ANHYDROUS ACETIC ACID IN SUCH AMOUNT THAT AT LEAST APPROXIMATELY 4 MOLECULAR PROPORTIONS OF ACETIC ACID ARE PRESENT FOR EACH MOLECULAR PROPORTION OF N-ACETYLANTHRANILIC-ACETIC ANHYDRIDE, WHEREBY N-ACETYLANTHRANILE ACID AND ACETIC ANHYDRIDE ARE FORMED, AND SUBSEQUENTLY RECOVERING THE RESULTING N-ACETYLANTHRANILIC ACID. 